Pursuit of next-generation glycopeptides: a journey with vancomycin

Vancomycin, a blockbuster antibiotic of the glycopeptide class, has been a life-saving therapeutic against multidrug-resistant Gram-positive infections. The emergence of glycopeptide resistance has however enunciated the need to develop credible alternatives with potent activity against vancomycin-resistant bacteria. Medicinal chemistry has responded to this challenge through various strategies, one of them being the development of semisynthetic analogues. Many groups, including ours, have been contributing towards the development of semisynthetic vancomycin analogues to tackle vancomycin-resistant bacteria. In this feature article, we have discussed our research contribution to the field of glycopeptides, which includes our strategies and designs of vancomycin analogues incorporating multimodal mechanisms of action. The strategies discussed here, such as conferring membrane activity, enhanced binding to target, multivalency, etc. involve semisynthetic modifications to vancomycin at the carboxy terminal and the amino group of the vancosamine sugar of vancomycin, to develop novel analogues. These analogues have demonstrated their superior efficacy in tackling the inherited forms of vancomycin resistance in Gram-positive and Gram-negative bacteria, including highly drug-resistant strains. More importantly, these analogues also possess the ability to tackle various non-inherited forms of bacterial resistance, such as metabolically dormant stationary-phase and persister cells, bacterial biofilms, and intracellular pathogens. Our derivatives also display superior pharmacokinetics, and less propensity for resistance development, owing to their different modes of action. Through this feature article, we present to the reader a concise picture of the multitude of approaches that can be used to tackle different types of resistance through semisynthetic modifications to vancomycin. We have also highlighted the challenges and lacunae in the field, and potential directions which future research can explore.